Another endocrine gland susceptible to destruction by autoimmunity, infection, and bleeding is the adrenal gland. Because oral replacement of cortisol does not accurately reproduce the pattern of cortisol secretion by the native adrenal gland, the generation of adrenal cells from stem cells would be of therapeutic benefit.
The only transcription factor that has been expressed in ES cells to help direct differentiation along a steroidogenic cell lineage is steroidogenic factor 1 (SF-1)
(46). SF-1 is an orphan member of the steroid receptor superfamily (reviewed in
(47). It is expressed in a variety of tissues, including the adrenal cortex, testis (Sertoli cells), ovary (granulosa and theca cells), the placenta, and the pituitary and hypothalamus. During development, SF-1 is expressed in the urogenital ridge as early as embryonic day 9 in mice, and its role in the differentiation of steroidogenic tissues is demonstrated by the absence of adrenal glands and gonads in mice with a null mutation of the SF-1 gene (48,49). In humans, mutations in SF-1 are associated with hypogonadism and hypoadrenalism (47). Among the targets of SF-1 are the genes that encode the steroidogenic cytochrome P450 enzymes (47).
Given the role of SF-1, it is not surprising that its expression in ES cells directs their differentiation toward a steroidogenic phenotype (46). The morphology of ES cells stably transfected with a vector expressing SF-1 changes from birefringent spheres into flat, phase-dull sheets despite the continued presence of mouse embryo fibroblast feeder cells and leukemia inhibitory factor, both of which prevent ES cell differentiation. Among the factors known to induce steroidogenesis in steroidogenic cell lines are retinoic acid and cyclic adenosine 5'-monophosphate, which is the downstream effector of hormones such as adrenocorticotropic and luteinizing hormones. Treatment of the SF-1-express-ing ES cells with a cyclic adenosine 5'-monophosphate analogue with or without retinoic acid markedly increased expression of the rate-limiting steroidogenic enzyme P450 side-chain cleavage (P450scc), an effect not observed in native ES cells (46). Moreover, in cells provided with 20a-hydroxycholesterol, a substrate for P450scc, progesterone was synthesized in amounts proportional to the expression of P450scc mRNA. It is important to note that this change in cell phenotype occurred despite the continued presence of mouse embryo fibroblasts and leukemia inhibitory factor. Thus SF-1 expression is capable of initiating a program that converts ES cells into steroidogenic cells and may serve to augment the development of steroidogenic tissues from stem cells.
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